ROS-responsive core–shell microgels for phase-specific treatment of myocardial infarction via programmed drug delivery

Pathology of myocardial infarction (MI) undergoes continuous spatiotemporal transformation, during which immediate elevated reactive oxygen species (ROS) and subsequent upregulated connective tissue growth factor (CTGF) exacerbate the impairment of cardiac functions. The major challenge lies in designing biomaterials that can adaptively respond to the temporal changes in the MI microenvironment. Herein, we prepared ROS-responsive dual drug-loaded core–shell microgels (SaB/Cand@C-S MGs) using microfluidic chip technology. The hydrogel shell was made from ROS-eliminating hyperbranched poly(acrylate-capped thioketone-containing ethylene glycol) (HBPAK) and methacrylated hyaluronic acid (HAMA), which was further encapsulated with hydrophilic salvianolic acid B (SaB). The oleogel core was loaded with hydrophobic candesartan (Cand). This structure enabled programmed drug release by utilizing ROS-responsive shell. The release of Cand from the SaB/Cand@C-S MGs in vitro was significantly accelerated in the presence of H 2 O 2 , reaching to 68% over 21 d, compared to 24% in PBS. In a rat MI model, minimally invasive injection of the SaB/Cand@C-S MGs into the infarcted area demonstrated both short-term anti-inflammatory effect and long-term benefit in fibrosis suppression. This phase-targeted approach ultimately resulted in improved cardiac functions, reduced fibrosis, and decreased ventricular dilation. The core–shell microgels as a drug reservoir offer a programmed drug delivery strategy adaptive to the specific phases of MI, showing great potential for applications.